Project Summary/Abstract A significant obstacle to developing effective drug addiction therapies is that drug-induced neuronal plasticity may be restricted to discrete neuronal populations within brain reward areas. The processes driving selection of specific cells from a larger pool of available neurons are not clear. Our long-term goal is to identify the mechanisms that assemble medium spiny neuron (MSN) microcircuits underlying behavioral expression of cocaine seeking and taking. In this application, our objective is to identify cocaine-related neuronal adaptations that depend on astrocytic signaling. We propose a hypothesis that astrocytic signals recruit discrete subpopulations of MSNs within the nucleus accumbens (NAc) shell to facilitate neuronal and behavioral plasticity associated with cocaine self-administration in the rat. This hypothesis is supported by our preliminary and published data and studies from other groups. The rationale for pursuing this hypothesis is that despite a growing recognition that astrocytes actively modulate neuronal activity, little is known about the role of astrocytes in coordination of local circuits and even less about regulation of local circuits by cocaine. On the basis of substantial preliminary data we will test our central hypothesis in three specific aims: 1) Characterize the impact of astrocyte signaling on cocaine-induced NMDA receptor (NMDAR) plasticity in MSN microcircuits. 2) Characterize the impact of astrocyte signaling on cocaine-induced AMPA receptor (AMPAR) plasticity in synchronously active MSNs. 3) Identify the consequences of astrocyte-synchronized neuronal activity on cocaine seeking and taking. In the first aim, we will use a unique characteristic of neuronal response to astrocyte-derived signals, slow inward currents (SICs), to test the hypothesis that cocaine-induced plasticity of extrasynaptic NMDARs, previously linked to cocaine exposure, is restricted to NAc shell MSNs displaying SIC events. The second aim is built on classical knowledge linking NMDAR-mediated signaling to plasticity of synaptic AMPARs and current evidence indicating that NMDAR-mediated SICs co-occur in neuronal subpopulations. In this aim, we will determine whether cocaine-induced plasticity of synaptic AMPAR signaling is restricted to subpopulations of NAc shell MSNs synchronized by astrocyte-derived signals. In the third aim, we will test the hypothesis that facilitation and inhibition of astrocyte-driven neuronal synchronization will, respectively, facilitate and inhibit cocaine-seeking behaviors. The approach is significant because it improves our ability to identify cell populations responsible for specific behavioral responses. This ability is critical for targeted therapeutic approaches. Our approach is innovative because: it considers a novel hypothesis of astroglia as active participants in selection of cocaine-relevant neuronal microcircuits, it facilitates development of novel viral tools to identify such microcircuits, and it seeks to identify novel mechanisms of cocaine-induced neuroglial plasticity. Completion of these studies will expand understanding of the relationship between glial signaling, individual neuron excitability, local network function, and behavioral outcomes in the context of cocaine addiction.